Recent data suggest that the glomerular epithelial cell, or podocyte plays a critical role in the function of the blood filter. More importantly, the pathogenesis of a wide variety of glomerular diseases is thought to be secondary to podocyte dysfunction. Little is known, however, about the function of podocytes in glomerular filtration and disease. The focus of this grant application is on CD2AP, an intracellular molecule that we originally discovered as a component of the immune system. CD2AP, however, is highly expressed in podocytes and CD2AP deficient animals die of nephrotic syndrome. This suggests a critical role for CD2AP in podocyte function. Most data suggest that CD2AP is involved in cytoskeletal regulation and in the process of endocytosis and intracellular trafficking. CD2AP heterozygosity appears to be linked with accumulation of immunoglobulin and immune complexes in the glomerular basement membrane (GBM). Based on this data, our current hypothesis proposes that the kidney filter is permeable to serum proteins and that the role of the podocyte is to transport this protein into the urinary space. We postulate that decreased clearance of proteins within the GBM leads to increased susceptibility to immune mediated damage. To test this hypothesis, we propose four specific aims. In the first, we wish to determine whether the accumulation of protein in the GBM leads to increased susceptibility to renal injury by nephrotoxic antibodies or immune complexes. In the second, we investigate how the podocyte might transfer proteins from the GBM to the urinary space and focus on a receptor for albumin and immunoglobulin expressed in podocytes called the neonatal Fc receptor. Third, we speculate that the handling of large volumes of fluid and protein will require an efficient process for internalization and therefore propose to analyze the process of macropinocytosis in podocytes. Lastly, we propose to determine the role of the CD2AP orthologue, Cin85, in the podocyte by generating a conditional Cin85 deficient mouse. We hope that understanding the function of the podocyte will allow a better understanding of the pathogenesis of glomerular diseases which will hopefully lead to more effective therapies for this important class of debilitating diseases.